CH631993A5 - METHOD FOR PRODUCING NEW ANHYDRO SUGAR. - Google Patents

Description

The invention relates to a process for the preparation of new 1,6-anhydro-β-D-hexopyranose derivatives of the formula I.

40

45

R / r ~ 0 - Cli

(I)

55

60

65

wherein R2 is hydrogen or acyl, R3 and R4 represent alkyl, alkenyl or aralkyl radicals with the proviso that one of the two radicals R3 and R4 is an aroyl radical, when R2 is hydrogen, R4 can also be hydrogen, with the further proviso that the radicals R3 and R (together contain at least 3 carbon atoms, and if R4 represents the benzyl radical, the radical R3 contains at least 2 carbon atoms.

In U.S. Patent No. 3.914.212 describes anhydrofura-nose derivatives with fibrinolytic and thrombolytic and, depending on the acyl residues of carboxylic acids present as substituents, also anti-inflammatory properties. The known substances are structurally similar to the compounds of the present invention, but do not affect the novelty of the latter.

631 993

The new anhydro-pyranose derivatives of the formula I belong to the Altro, Gulo, Ido or Talo, in particular the Allo, Galakto or Manno and primarily the Gluco series.

Lower residues are in particular those with 1-7 C atoms, especially with up to 4 C atoms.

Aldyl is especially lower alkyl, e.g. As ethyl, isopropyl, straight-chain or branched, butyl, pentyl, hexyl or heptyl bound in any position and especially methyl or n-propyl.

Alkenyl is especially lower alkenyl, e.g. Isopropenyl, 2-methallyl, 3-butenyl and especially allyl.

Aralkyl is in particular aryl-lower alkyl, the lower alkyl part above all having the above meaning and being primarily methyl, the aryl part being 1- or 2-naphthyl or especially phenyl, which are optionally substituted, such as by halogen, in particular bromine and primarily chlorine, lower alkyl, lower alkoxy, trifluoromethyl, and / or hydroxy, the aryl part bearing several, such as two or three, but preferably one, especially in the 4-position, or being unsubstituted.

Lower alkoxy radicals include, in particular, ethoxy and propoxy, iso-propoxy or especially methoxy radicals.

Acyl is in particular an acyl residue of an organic acid, in particular an organic carboxylic acid. So acyl is especially alkanoyl, especially lower alkanoyl, such as acetyl or propionyl, or also aroyl, such as naphthoyl-1, naphthoyl-2 and especially benzoyl or benzoyl substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or lower alkanoyloxy, such as salicyloyl or o Acetylsalicyloyl, and pyridylcarbonyl, for example Nicotinoyl, or an acyl residue of an organic sulfonic acid, e.g. an alkanesulfonic acid, in particular a lower alkanesulfonic acid, such as methanesulfonic acid or ethanesulfonic acid, or an arylsulfonic acid, in particular an optionally lower alkyl-substituted phenylsulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid, and also carbamoyl, such as unsubstituted carbamoyl, lower alkylcarbamoyloyl or arylcarbamoylamylcarbamoylamylcarbamoyl or arylcarbamoylamylcarbamoyl or arylcarbamoylamylcarbamoyl or arylcarbamoylamylcarbamoyl or phenyl-carbamoyl.

However, acyl is also an acyl radical of an antiinflammatory carboxylic acid, in particular an acyl radical of the formula II

Fibrinolytic and thrombolytic efficacy also manifests itself in a test on normal rats according to the publication by M. Rüegg, L. Riesterer and R. Jaques. Pharmacology, 4,242-254 (1970), in a shortening of the 5 euglobulin clot lysis time at a dose of 3 to 30 mg / kg.

With regard to their effectiveness, compounds of the formula in particular are

10th

15

Ar

R £

CH

(Ia)

20th

to emphasize in which R2, R3 and R4 have the abovementioned meaning, and the corresponding compounds of the formula

25th

30th

35

CH,

R, o 4I

C.

I.

H

C - '\

OR.

-0

c-I

H

O

(Ib).

OR,

CO

(II)

wherein R5 represents a hydrogen atom or a lower alkyl radical, in particular the methyl radical, and Ar represents a phenyl or naphthyl radical, which is preferably substituted by cycloalkyl, cycloalkenyl, aryl, lower alkyl, lower alkoxy, phenyloxy, halogen, pyrrolino and / or hydroxy groups can be substituted.

Cycloalkyl as a substituent of the phenyl radical Ar is, for. B. mono-, bi- or polycyclic cycloalkyl with z. B. up to 12, such as 3-8, preferably 5-8 ring carbon atoms, in particular cyclopentyl or cyclohexyl.

Cycloalkenyl as a substituent of the phenyl radical Ar is, for. B. a monocyclic cycloalkyl having 3-8, preferably 5-8-ring carbon atoms, especially cyclohexenyl or cyclopentenyl.

Lower alkyl as a substituent of the radical Ar is, in particular, lower alkyl specified for R2, especially methyl.

The new compounds have valuable pharmacological properties.

For example, the anhydropyranose derivatives produced according to the invention show, in particular, fibrinolytic and thrombolytic effects, as can be shown in animal experiments, e.g. B. with oral administration of about 0.1 to about 5 mg / kg, in particular from about 0.3 to about 3 mg / kg, on the kaolin paw edema rat. The

Compounds of the formula (Ia) and of the formula (Ib) in which R 2 is hydrogen or a lower alkanoyl or aroyl radical and R 3 is a lower alkyl or aryl-lower alkyl radical and R 4 is hydrogen, a lower alkyl, alkyl-lower alkyl are particularly effective - or aroyl radical, with the proviso that the radicals R3 and R4 together contain at least 3 carbon atoms and if R4 represents the benzyl radical, the radical R3 contains at least 2 carbon atoms 45 and, if R4 is an aroyl radical, R2 is hydrogen.

Particular mention should be made of those compounds of the formula (Ia) and of formula (Ib) in which R3 represents a benzyl radical and R2 and R4 have the abovementioned meaning, with the proviso that if R4 represents an aroyl radical, R2 is hydrogen-50.

Their effectiveness can be shown in the kaolin paw breath test on the rat in the case of oral administration. B. the 1,6-anhydro-3,4-di-0-benzyl-β-D-glucopyranose or the 1,6-anhydro-3-O-benzyl-β-D-glucopyranose at doses from 0.3 to 3 55 mg // kg cause a pronounced reduction in the euglobulin clot lysis time.

The new compounds can therefore be used as fibrinolytics and thrombolytics.

60 The new compounds with an acyl radical of formula II of an anti-inflammatory carboxylic acid as radical R2 also show novel anti-inflammatory and antinoci-ceptive (analgesic) effects with low toxicity. For example, these new compounds show in the adjuvant arthritis test [based on that of Newbould, Brit. J.Pharmacol., Vol. 21, pages 127-136 (1936) described methods] in rats with pronounced anti-inflammatory effects when administered orally. The new compounds can therefore also be used as anti-

631 993 4

flammatory (anti-inflammatory), e.g. antiexsudative or vascular permeability, primarily as antiarthritic and analgesic compounds, in particular for the treatment of rheumatic inflammation.

The new anhydropyranoses are produced according to known methods.

So the new anhydropyranose derivatives are prepared by that in a corresponding compound of the formula

20th

in the β-D form, in which, if the acyl radical is introduced, R2 'is hydrogen, and R3' and R4 'have the meanings of R3 and R4 except the aroyl radical, and, if the aroyl radical is introduced, R2' and one of the R3 'and R4' are hydrogen, and the other of the two R3 'and R4' is R3 and R4, with the exception of the aroyl radical,

introduces an acyl radical R2 or an aroyl radical R3 or R4 by reaction with an acid corresponding to the acyl radical or aroyl radical or a reactive functional derivative thereof.

An acyl radical R2 or an aroyl radical R3 or R4 is introduced into a compound of the formula III with free hydroxy groups, in particular according to known acylation processes, by preferably a compound of the formula III with an acid corresponding to the acyl or aroyl radical with a corresponding reactive functional derivative thereof.

A preferably used acid derivative is in particular an anhydride of a carboxylic acid, including a mixed anhydride, such as the anhydride with a hydrohalic acid, e.g. Hydrochloric acid or the anhydride with a carboxylic acid lower alkyl half ester (which can be obtained, for example, by reacting a suitable salt, such as an ammonium salt of the acid with a lower alkyl haloformate, e.g. ethyl chloroformate), or with a suitable optionally substituted lower alkane carboxylic acid, e.g. Trichloroacetic or pivalic acid, also an activated ester of such an acid, e.g. An ester with an N-hydroxy amino or N-hydroxyimino compound such as N-hydroxy succinimide, or with an electron attractive group, e.g. Nitro, 50 acyl, such as lower alkanoyl, e.g. acetyl, or aroyl, e.g. Benzene groups, or optionally functionally modified carboxy groups such as carbo-lower alkoxy, e.g. Carbomethoxy or carbethoxy groups, carbamoyl, e.g. N, N-dimethyl-carbamoyl, e.g. Lower alkanol, in particular methanol, or phenol, e.g., N, N-dimethyl-carbamoyl groups or 55 cyano groups, e.g. Cyanomethanol or 4-nitrophenol.

If necessary, one works in the presence of a suitable condensing agent and / or catalyst. An acid can e.g. in the presence of a dehydrating condensing agent such as a carbodiimide, e.g. Dicyclohexylcarbodi-imide, optionally together with a catalyst, such as a copper salt. e.g. Copper I or copper II chloride, or a ß-alkynylamine or Nideralkoxyacetylenverbindung, an acid halide z. E.g. in the presence of a basic acid-binding 6S condensing agent such as pyridine or tri-lower alkylamine, e.g. Triethylamine, and an anhydride e.g. in the presence of a suitable base such as pyridine, tri-lower alkylamine or optionally an acidic catalyst such as zinc chloride.

The new compounds can be present as diastereoisomer mixtures or in the form of the pure isomers. The separation of isomer mixtures obtained into the pure isomers can be carried out by the known methods.

The process described above is carried out according to methods known per se, in the absence or preferably in the presence of diluents or solvents, if necessary, with cooling or heating, under elevated pressure and / or in an inert gas such as nitrogen atmosphere.

Taking into account all substituents in the molecule, if necessary, especially in the presence of easily hydrolyzable O-acyl residues, particularly gentle reaction conditions, such as short reaction times, use of mild acidic or basic agents in low concentration, stoichiometric quantitative ratios, choice of suitable catalysts, solvents, Temperature and / or pressure conditions apply.

The starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.

The starting materials are known and / or can be prepared by methods known per se, e.g. with the ring closure described above or by etherification or esterification of an anhydropyranose.

The following examples illustrate the invention described above; However, sid should not restrict their scope in any way. Temperatures are given in degrees Celsius.

example 1

A solution of 47.7 g of l, 6-anhydro-3,4-di-0-benzyl-β-D-glucopyranose in 250 ml of pyridine is added dropwise with 18.5 ml of benzoyl chloride and left to stand at about 25 ° for 16 hours. 10 ml of water are added and the main amount of pyridine is evaporated off in a water jet vacuum after 30 minutes. The flask residue is mixed with ether and water, the ether phase is washed with ice-cold 2N hydrochloric acid, a dilute sodium carbonate solution and water, dried over magnesium sulfate and evaporated to dryness. The product crystallizes from ether / petroleum ether and is recrystallized from ethanol. The 1.6 anhydro-2-0-benzoyl-3,4-di-O-benzyl-β-D-glucopyranose of F. 78-79 °, of the Rf value 0.28 on silica gel thin-layer plates in the system Ether / petroleum ether 1/1 and the optical rotation [a] o = + 9 ° ± 1 ° (chloroform, c = 1.048).

The starting material used can be produced as follows:

a) A solution of 44.7 g of ethyl-2-0-allyl-3-0-benzyl-6-0-trityl-β-D-glucopyranoside in 100 ml of dimethyl sulfoxide is stirred with moisture in a nitrogen atmosphere with 10 g of potassium hydroxide powder offset and heated to 60 °. A solution of 10.8 g of benzyl chloride in 20 ml of dimethyl sulfoxide is then added dropwise over a period of 6 hours, and the mixture is stirred at 60 ° for a further 2 hours. This approach is cooled and poured onto ice water. It is extracted with ether, the organic phase is washed neutral with water, dried over magnesium sulfate and evaporated to dryness. The ethyl-2-O-allyl-3,4-di-0-benzyl-6-0-trityl-aD-glucopyranoside is obtained as a yellow oil with an Rf value of 0.55 from silica gel thin-layer plates in the ether / petroleum ether system (1 / 1)

b) A solution of 62 g of ethyl-2-0-allyl-3,4-di-0-benzyl-6-O-trityl-aD-glucopyranoside in 3.11 benzene is mixed with 31 g of p-toluenesulfonic acid monohydrate for 30 minutes Reflux stirred. After cooling, this solution is washed with 230 ml of 1N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated to dryness. The backlog will

5,631,993

column chromatography neutral on 1 kg aluminum oxide, Akti hours at about 22 ° C allowed to stand. There are now 10 ml vitätsstufe I cleaned with methylene chloride as the eluent. Ice water and evaporates most of the pyridine. The 1,6-anhydro-2-0-allyl-3,4-di-O-benzyl-ß-Dglu residue is obtained and is taken up in ether and this copyranose with an Rf value of 0.26 is washed on a thin layer of silica gel solution with water, ice-cold 2N hydrochloric acid, water, one sown in the ether / petroleum ether system (1/1), from the body. 175 ° / 0.03 torr and saturated sodium bicarbonate solution and water, drying the optical rotation [a] o = -19 ° ± 1 ° (chloroform, c = 1.019) over magnesium sulfate and evaporating the solvent. The c) A solution of 29.5 g of 1,6-anhydro-2-0-allyl-3,4-di-O- remaining 1,6-anhydro-2-0-benzoyl-3,4-di-O -benzyI-ß-benzyl-ß-D-glucopyranose in 82 ml of dimethyl sulfoxide is crystallized from ether / petroleum ether in D-mannopyranose; in a nitrogen atmosphere with 4.3 g of potassium tert-butoxide 30 mp 72.5-73 ° C, Rf value 0.15 on silica gel thin-layer plates, stirred at 100 ° for minutes. After cooling, the io is poured into the system methylene chloride, [a] o = + 58 ° ± 1 ° (chloroform, c = reaction mixture on ice water and extracted with ether. Die 1,123).

The ether phase is washed with water, over magnesium sulfate. The starting material can be prepared as follows: dried and evaporated to dryness. The 1.6- a) A solution of 17 g of 1,6-anhydro-3,4-di-O-benzyl-ß-D-

Anhydro-3,4-di-0-benzyl-2-0-propenyl-ß-D-glucopyranose glucopyranose in 150 ml absolute dimethylformamide and the Rf value 0.38 on silica gel thin-layer plates in the system is 14.2 ml absolute dimethyl sulfoxide with stirring and ether / petroleum ether (1/1). Moisture exclusion with 14.2g phosphorus pentoxide portions -

d) A solution of 25.3 g of 1,6-anhydro-3,4-di-0-benzyl-2-0- was added. This reaction mixture is now 4 hours with propenyl-β-D-glucopyranose in 200 ml of acetone, stirred with 10 ml of 1-n 60 ° C, cooled and mixed with 250 ml of saturated hydrochloric acid and kept at 50 ° for 30 minutes. One cools sodium bicarbonate solution poured. It is extracted with the solution, neutralized with 1N sodium hydroxide solution and evaporated to chloroform, the organic phase is washed with water and dried to dryness. The residue is taken up in ether, with this over magnesium sulfate and the solvent is evaporated. Washed water, dried over magnesium sulfate and freed from the resulting 1,6-anhydro-3,4-di-O-benzyl-ß-D-arabino solvent. The residue is purified by column chromatography-hex-2-ulo-pyranose with an Rf value of 0.63 on a thin layer of silica gel on 1 kg of silica gel with ether / petroleum ether (1/1). plates in the methylene chloride / ethyl acetate 85:15 system is dried in the 1,6-anhydro-3,4-di-O-benzyl-ß-D-glucopyra-25 high vacuum.

nose as a yellowish oil with an Rf value of 0.10 on silica gel thin- b) A solution of 15.2g 1,6-anhydro-3,4-di-O-benzyl-ß-

Layered plates in the ether / petroleum ether (Vi) system and the opti-D-arabino-hex-2-ulo-pyranose in 150 ml of methanol dropwise turn wise within 3 hours to a solution cooled to 0 ° C

[a] g> = -36 ° ± 1 ° (chloroform, c = 0.955). of 2 g sodium borohydride in 90 ml methanol / water 3: 1

30 ben. The mixture is stirred for 1 hour in an ice bath, 30 ml of acetone are added and the solvent is evaporated off. The residue is taken up in ether Example 2, washed with water, dried over magnesium sulfate and the solvent evaporated. You get that

A solution of 13.5 g of 1,6-anhydro-3,4-di-O-benzyl-β-D-1,6-anhydro-3,4-di-O-benzyl-β-D-mannopyranose from Rf Manopyranose in 150 ml of pyridine is added dropwise with 5 ml of benzoyl chloride and 18 lene chloride / ethyl acetate 85:15 with moisture.

I.

t

M

Claims (8)

631 993 PATENT CLAIMS 1. Process for the preparation of new 1,6-anhydro-β-D-hexopyranose derivatives of the formula CH_ 0 A- R.-O-CH H \ nCHOR3-CHOR2 (I) 10th in which R2 is hydrogen or acyl, R3 and R4 represent alkyl, alkenyl or aralkyl radicals with the proviso that one of the two radicals R3 and R4 represents an aroyl radical, when R2 is hydrogen, R4 also represents hydrogen, with the further proviso, that the radicals R3 and R4 together contain at least 3 carbon atoms and if R4 represents the benzyl radical, the radical R3 contains at least 2 carbon atoms, characterized in that one in a corresponding compound of the formula CH. O A -OCH H V CHOR3-CHOR2 > (III) H 35 in the β-D form, in which, if the acyl radical is introduced, R2 'is hydrogen and R3' and R4 'have the meanings of R3 and R4 except the aroyl radical, and, if the aroyl radical is introduced, R2' and one of the R3 'and R4' are hydrogen and the other of R3 'and R4' is R3 and R4 except for the aroyl group, introduces an acyl radical R2 or an aroyl radical R3 or R4 by reaction with an acid corresponding to the acyl radical or aroyl radical or a reactive functional derivative thereof. 2. The method according to claim 1, characterized in that obtained diastereomer mixtures of the formula I are separated into the pure isomers. 2nd or compounds of the formula 3. The method according to claim 1, characterized in that reacting a compound of the formula III with a corresponding acid in the presence of a dehydrating condensing agent, optionally together with a catalyst. 4 \ ■ & X / -i: (Ia) I. H I. OR. (Ib) 15 20th 25th 30th produces in which R2, R3 and R4 have the meanings given under formula I. 4. The method according to claim 1, characterized in that 50 a compound of the formula III is reacted with a corresponding acid halide in the presence of a basic, acid-binding condensing agent. 5. The method according to claim 4, characterized in that reacting an acid chloride in the presence of pyridine. 6. The method according to any one of claims 1 -5, characterized in that compounds of the formula fV ï / r— \ 7. The method according to any one of claims 1-6, characterized in that compounds of the formula Ia or Ib are prepared in which R2 is hydrogen or a lower alkanoyl or aroyl radical and R3 is a lower alkyl or aryl-lower alkyl radical and R4 is hydrogen, one Lower alkyl, aryl-lower alkyl or aroyl radical, with the proviso that the radicals R3 and R4 together contain at least 3 carbon atoms and, if R4 represents the benzyl radical, the radical R3 contains at least 2 carbon atoms and, with the further proviso that R4 represents an aroyl radical if, R2 is hydrogen. 8. The method according to any one of claims 1-6, characterized in that compounds of the formula Ia or Ib are prepared in which R3 represents a benzyl radical and R2 and R4 have the meaning given under formula I, with the proviso that R4 represents an aroyl radical when R2 is hydrogen.